These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.

/pdf/langerhans-cell-histiocytosis-lch-guidelines-for-diagnosis-tpou7tilf7.pdf

Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical Work-Up, and Treatment for Patients Till the Age of 18 Years

The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewing's Sarcoma Study (CESS 81) using a four-drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease-free. Using the Kaplan-Meier life table analysis, the estimated disease-free survival (DFS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty-one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3-year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewing's sarcoma of bone.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819880101%2961%3A1%3C23%3A%3AAID-CNCR2820610106%3E3.0.CO%3B2-M

Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial.

Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogenous group of tumors, often lacking known genetic abnormalities. On the basis of a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSKs are characterized by BCOR exon 16 internal tandem duplications (ITDs), whereas a smaller subset shows YWHAE-NUTM2B/E fusions. Because of overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCSs and 7 PMMTIs selected, RNA sequencing was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR), and BCOR ITD by PCR. A control group of 4 CCSKs and 14 URCSs in older children or adults without known gene fusion and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, whereas BCOR ITD was lacking. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl with a back lesion. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITDs, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK cases but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures, and varying degree of myxoid change were occasionally seen. BCOR ITD-positive tumors occurred preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared with other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI cases, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features, and genetic signature, thus raising the possibility of a soft tissue counterpart to CCSK.

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney.

Langerhans cell histiocytosis is a disease which frustrates both clinician and scientist Its aetiology is unknown, its pathogenesis is ill understood and the clinical course is unpredictable Historically, the different nomenclatures reflecting the first clinical descriptions by Hand (1893, 1921), Schuller (1915) and Christian (1920), and subsequently by Letterer (1924) and Siwe (1933), led to confusion only partially resolved by Lichtenstein (1953) who recognised that the disease in each of these clinical syndromes were components of a spectrum of disease involving the histiocyte He proposed his unifying concept of Histiocytosis X--'X' being the unknown aetiological factor In 1973, Nezelof recognised the lesional cell as a 'Langerhans-like' cell but it took another decade for the disease to be recognised as a single entity and the term Langerhans cell histiocytosis to be internationally accepted The publication, by the Histiocyte Society (1987), of their classification of the histiocyte disorders together with criteria for pathological diagnosis and clinical evaluation of Langerhans cell histiocytosis have consolidated the position This article details the wide variety of clinical manifestations of the disease and its sequelae and discusses possible epidemiological factors Finally it looks at the potential implications of recent scientific research on the management of the disease

Langerhans cell histiocytosis--clinical and epidemiological aspects.

Purpose : We present an update analysis of the multiinstitutional Ewing's sarcoma study CESS 86. Methods and Materials : From January 1986 through June 1991, 177 patients with localized Ewing's sarcoma of bone, aged 25 years or less, were recruited. Chemotherapy consisted of four 9-week courses of vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) in low-risk tumors (extremity tumors < 100 cm 3 ), or vincristine, actinomycin D, ifosfamide, and adriamycin (VAIA) in high-risk tumors (central tumors and extremity tumors ≥ 100 cm 3 ). Local therapy was an individual decision in each patient and was either radical surgery (amputation, wide resection) or resection plus postoperative irradiation with 45 Gy or definitive radiotherapy with 60 Gy (45 Gy plus boost). Irradiated patients were randomized concerning the type of fractionation in either conventional fractionation (once daily 1.8-2.0 Gy, break of chemotherapy) or hyperfractionated split-course irradiation simultaneously with the VACA/VAIA chemotherapy (twice daily 1.6 Gy, break of 12 days after 22.4 Gy and 44.8 Gy, total dose and treatment time as for conventional fractionation). For quality assurance in radiotherapy, a central treatment planning program was part of the protocol. Results : Forty-four patients (25%) received definitive radiotherapy ; 39 (22%) had surgery, and 93 (53%) had resection plus postoperative irradiation. The overall 5-year survival was 69%. Thirty-one percent of the patients relapsed, 30% after radiotherapy, 26% after radical surgery, and 34% after combined local treatment. The better local control after radical surgery (100%) and resection plus radiotherapy (95%) as compared to definitive radiotherapy (86%) was not associated with an improvement in relapse-free or overall survival because of a higher frequency of distant metastases after surgery (26 % vs. 29% vs. 16%). In irradiated patients, hyperfractionated split-course irradiation and conventional fractionation yielded the same results (5-year overall survival of definitively irradiated patients 63% after conventional fractionation and 65% after hyperfractionation ; relapse-free survival 53% vs. 58% ; local control 76% vs. 86%, not significant). The six local failures after radiotherapy did not correlate with tumor size or response to chemotherapy. Radiation treatment quality (target volume, technique, dosage) was evaluated retrospectively and was scored as unacceptable in only 1 out of 44 patients (2%) with definitive radiotherapy. Grade 3-4 complications developed in 4 out of 44 (9%) patients after definitive radiotherapy. Conclusions : Under the given selection criteria for local therapy, radiation therapy yielded relapse-free and overall survival figures comparable to radical surgery. Hyperfractionated split-course irradiation simultaneously with multidrug chemotherapy did not significantly improve local control or survival.

Radiation therapy in ewing's sarcoma: an update of the cess 86 trial

Background. Nineteen patients with Ewing sarcoma of bone, each younger than 3 years of age at the time of initial presentation, are reported. These children represent an unusually young age group for documented Ewing sarcoma and represent 2.6% of all patients registered in the Intergroup Ewing's Sarcoma Study (IESS).



Methods. The diagnosis was made on combined histologic, clinical, and radiographic grounds and was supported by immunohistochemistry in nine patients and electron microscopic study in eight patients. Immunohistochemical studies showed no staining against neuronspecific enolase, chromogranin, or S-100 in any patients, and in only one in nine patients were results of such studies focally positive against Leu-7.



Results. The most marked clinical variation between this group of infants and the general IESS patient population was a striking predominance of female patients in the younger age group (P < 0.001). There was a trend toward more rib, pelvis, and proximal long bone tumors in the infants and toddlers. The overall survival rate of theinfants was 56%, almost identical to the survival rates of the older children. All of the infants who died of disease did so within 4 years. Extended follow-up as long as 9.9 years has found no late deaths attributable to tumor. The most significant late complications of therapy included cardiotoxicity with cerebral embolization from the heart and a short lower limb secondary to radiation therapy.



Conclusions. Ewing sarcoma must be considered in the differential diagnosis of small cell, round cell, and blue cell tumors in bone, even in infants and toddlers.

Ewing sarcoma of bone in infants and toddlers. A clnicopathologic report from the intergroup Ewing's study

This report is a preliminary analysis of the local tumor control in 187 patients treated with multi-agent chemotherapy and local radiation therapy for non-metastatic Ewing's sarcoma. Patients were treated according to three different regimens, all of which included irradiation of the primary tumor and involved bone (5000-6000 rads in 5-6 weeks). The first group was treated with a combination of cyclophosphamide, vincristine, adriamycin and actinomycin-D. The second group received cyclophosphamide, vincristine and actinomycin-D. The third group was treated with cyclophosphamide, vincristine and actinomycin-D in addition to bilateral pulmonary irradiation. The present results, after a median follow-up of 24-30 months in the various groups combined, indicate that the local control is 87%. Twenty-two of 25 local failures appeared within 24 months (88% of recurrences). No difference in time of appearance of local recurrence was noted in the three treatment regimens. The highest incidence of local recurrence has been noted in the humerus (22%), the pelvis (19%), the tibia (14%) and the femur (11%). Sixty-seven of the 187 patients (35.8%) have developed distant metastases, mostly to the lungs and to other skeletal sites. Of the patients with pelvic primaries, 62% have developed distant metastases followed by the humerus (41%), the femur (36%) and the tibia (24%). A detailed analysis of radiation therapy technical factors was done in 110 patients with complete dosimetry data at the time of this report. There is a trend indicating that patients who received doses over 6000 rads (20/20) or with lower doses combined with chemotherapy containing adriamycin (9/9) have a higher local control. However, the difference with the other groups (67/81-83%) was not statistically significant. Radiation therapy in combination with multiple chemotherapy is an effective treatment method to control Ewing's sarcoma locally. The late effects of this intensive combined therapy must be assessed in long term survivals. Future studies in Ewing's sarcoma should attempt to elucidate crucial issues such as the optimal volume of bone that should be irradiated, the potential value of limited surgical resection of gross tumor and the determination of optimal multi-agent regimens which will enhance local tumor control and diminish distant metastases. Because of the rarity of this tumor, the need for cooperative controlled clinical trials is emphasized. Cancer 40:2864-2873, 1977.

Analysis of local tumor control in Ewing's sarcoma: preliminary results of a cooperative intergroup study.

Twenty-eight patients with histiocytosis X (HX) who had bone marrow aspirates and/or trephine biopsies taken at diagnosis were studied. Five of the 28 patients (18%) had bone marrow specimens with clusters of benign histiocytes characteristic of histiocytosis X. Several statistically significant clinical and laboratory differences were found between those patients with positive marrows versus those with uninvolved bone marrows. Presence of HX in the bone marrow was more frequently associated with fever (P less than 0.01), splenomegaly (P less than 0.01), rash (P = 0.04), diabetes insipidus (P = 0.09), and platelet counts less than 175 X 10(9)/L(P = 0.01). Two of the five patients with bone marrow involvement died, whereas there were no deaths due to HX in the other 23 patients. From this review, it is suggested that bone marrow involvement at diagnosis may be associated with more extensive and potentially fatal disease. HX of the marrow was more easily diagnosed from trephine biopsy sections than aspiration smears.

Bone marrow involvement in histiocytosis X.

Although these studies do not allow a definitive differentiation between the relative influence of chemotherapy and radiotherapy on mitogen-induced lymphocyte transformation, the data suggested both radiotherapy and chemotherapy can cause depression; however, radiotherapy may have a more pronounced effect. The relationship between the absolute peripheral blood lymphocyte count and phytohemagglutin and pokeweed mitogen-induced lymphocyte transformation was also analyzed. These data revealed that patients who are receiving or who have received intensive therapy may have normal peripheral absolute lymphocyte counts with impaired lymphocyte transformation. Serial studies of lymphocyte transformation were evaluated in 10 children with acute lymphoblastic leukemia who received both chemotherapy and radiotherapy.

The influence of sequential chemotherapy and radiotherapy on mitogen-induced lymphocyte transformation in patients with acute lymphoblastic leukemia.

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Ewing sarcoma of bone in infants and toddlers. A clnicopathologic report from the intergroup Ewing's study

Analysis of local tumor control in Ewing's sarcoma: preliminary results of a cooperative intergroup study.

Bone marrow involvement in histiocytosis X.

The influence of sequential chemotherapy and radiotherapy on mitogen-induced lymphocyte transformation in patients with acute lymphoblastic leukemia.